19-48965340-G-T

Position:

• chr19-48965340-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000146.4(FTL):​c.-168G>T variant causes a 5 prime UTR change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FTL NM_000146.4 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.53

Genes affected

FTL (HGNC:3999): (ferritin light chain) This gene encodes the light subunit of the ferritin protein. Ferritin is the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in this light chain ferritin gene are associated with several neurodegenerative diseases and hyperferritinemia-cataract syndrome. This gene has multiple pseudogenes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-48965340-G-T is Pathogenic according to our data. Variant chr19-48965340-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 16479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48965340-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.12). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTL	NM_000146.4	c.-168G>T		5_prime_UTR_variant	1/4	ENST00000331825.11	NP_000137.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FTL	ENST00000331825	c.-168G>T		5_prime_UTR_variant	1/4	1	NM_000146.4	ENSP00000366525.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 4

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary hyperferritinemia with congenital cataracts Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 19, 2013

- -

Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2022

This variant is also known as +32G>T. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters FTL gene expression (PMID: 9414300). ClinVar contains an entry for this variant (Variation ID: 16479). This variant has been observed in individual(s) with hyperferritinemia and cataracts syndrome (PMID: 9414300, 14662596, 23592921, 26849797). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the FTL gene. It does not change the encoded amino acid sequence of the FTL protein. -

FTL-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The FTL c.-168G>T variant is located in the 5' untranslated region. This variant has been reported in many individuals with autosomal dominant hyperferritinemia-cataract syndrome (Martin et al. 1998. PubMed ID: 9414300; Bennett et al. 2013. PubMed ID: 23592921; Cosentino et al. 2016. PubMed ID: 26849797). This variant occurs in the iron-responsive-element (IRE) of the FTL gene and distorts the loop structure, which disrupts binding with iron regulatory proteins and results in unregulated production of L-ferritin (Allerson et al. 1999. PubMed ID: 10473603; Brooks et al. 2002. PubMed ID: 11923255; Cosentino et al. 2016. PubMed ID: 26849797). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398124635; hg19: chr19-49468597;